T cell-mediated Immunity

Question 1

Can gammadelta T cells recognize non MHC bound antigens?

Answer 1

No, they bind to peptides/molecules presented on MHC-like proteins

Question 2

How is CD8/CD4 switched off during T cell maturation?

Answer 2

Both CD4 and CD8 are initially expressed during the “testing” stage and if the CD8 is activated as the coreceptor it stays that way and CD4 is removed and vice versa.

Question 3

How do microbes end up inside cells?

Answer 3

A: Microbes enter through phagocytosis by surviving inside and escaping into cytoplasm

B: Viral binding of receptors and entry into cytoplasm

Question 4

What other functions do T cells do in addition to defense against intracellular pathogens?

Answer 4

T lymphocytes are important for defense against larger extracellular pathogens like bacteria, fungi, and helminths.

The subset of CD4 cells that do this were unknown when classic role of T cells was first defined. A major role of these subsets is to help B cells produce antibodies. Another role is to promote inflammation that is rich in activated leukocytes that are particularly efficient at killing extracellular microbes.

Question 5

Potential short answer questions on the exam:

Answer 5

The signals needed to activate T lymphocytes, and cellular receptors used to
sense and respond to these signals
– How the few naive T cells specific for any microbe gets converted into large
number of effector T cells that have specialised functions and ability to eliminate
diverse microbes?
– The molecules produced by T lymphocytes that mediate their communications
with other cells, such as macrophages, B lymphocytes, and other leukocytes?

Question 6

What are the 3 phases of T cmi?

Answer 6

Induction of response: Naive CD4+ T cells and CD8+ T cells recognise peptide antigens presented by APCs in peripheral lymphoid organs. T cells proliferate and differentiate into effector cells.

Migration of effector T cells and other leukocytes to site of antigen

T cell effector functions

Question 7

How are activated T cells guided to the site of the antigen?

Answer 7

Effector T cells and other leukocytes migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues

Question 8

What are the T cell effector functions?

Answer 8

CD4+ T cells recruit and activate phagocytes to destroy microbes

CD8+ cytotoxic T cells kill infected cells and can also activate macrophages

Question 9

What are the 3 critical stimuli for full T cell activation?

Answer 9

Antigen recognition initiates process

Co-stimulation maximises response

Cytokines amplify response and direct it along various specialised differentiation pathways

Question 10

What are the phases of T cell response?

Answer 10

Antigen recognition, activation and cytokine secretion.

Some cytokines stimulate proliferation of antigen-activated T cells (clonal expansion) and differentiation into effector T cells.

Question 11

What does IL-2 do?

Answer 11

Acts on itself to stimulate proliferation/clonal expansion.

IL-2 is also known as a T Cell growth factor

Question 12

What can T cells differentiate into?

Answer 12

Effector T cells (CD4+ helper)

Memory T cell

Question 13

Where do effector T cells go after being activated?

Answer 13

Many leave lymphoid organs through blood and migrate to infected tissue and eradicate microbes while others provide signals to B cells that promote antibody responses against microbes.

Question 14

What receptors and membrane proteins are involved in binding of MHCII and T cell activation?

Answer 14

TCR binds to peptide+MHCII

CD4 - MHCII invariant region

Zeta chain and CD3 bind closely to TCR forming the TCR complex

LFA-1 binding ICAM-1 (same as neutrophil and extravasion)

CD28 binding B7-1/B7-2

Question 15

What membrane proteins are important for T cell adherence to endothelium?

Answer 15

VLA-4 binding VCAM-1

Question 16

What are superantigens?

Answer 16

Polyclonal activators of T cells that activate many different T cells.

Question 17

What kind of problem can superantigens lead to?

Answer 17

Systemic inflammatory disease due to excessive production of cytokines from many T cells.

Question 18

Why is low affinity selected for with TCRs?

Answer 18

Adhesion molecules on T cells recognize ligands on APCs and stabilise binding of T cells to APCs for long enough for signalling threshold to be achieved.

Question 19

What is LFA-1 and what does it bind to?

Answer 19

Leukocyte function-associated antigen 1 (LFA-1) which binds to ICAM-1. (IntraCellular Adhesion Molecule 1)

Question 20

What family of proteins is LFA-1 associated with?

Answer 20

Heterodimeric (2-chain) proteins known as integrins

Question 21

What receptors are important for co-stimulation of T cells?

Answer 21

Best-defined co-stimulators for T cells are B7-1 (aka CD80) and B7-2 (aka CD86) which bind to CD28 on all T cells.

Question 22

Which cells have CD28?

Answer 22

Virtually all T cells

Question 23

Which cells have B7 receptors (aka CD80 and CD86)?

Answer 23

T cells, B cells, dendritic cells, macrophages.

APCs in general.

Question 24

What happens during co-stimulation?

Answer 24

APC presents antigen on MHCII (via TCR and CD4) in addition to this there must be binding between B7-1/2 and CD28 which results in activation of T cell and in return IL-12 is produced which activates T cell and allows it to proliferate and differentiate.

Question 25

How do adjuvants help with creating immune memory?

Answer 25

They induce expression of co-stimulators on APCs and stimulate secretion of cytokines. It boosts activation of Pattern Recognition Receptors (PRRs such as TLRs) activation by administering microbes or microbe like molecules. They trick immune system into responding to purified protein antigens.

Question 26

What does artificially blocking co-stimulation help with?

Answer 26

Agents that block B7:CD28 are used to treat rheumatoid arthritis, inflammatory disease and graft rejections. Antibodies blocking CD40:CD40L are being tested in inflammatory diseases and transplant recipients.

Question 27

What use is there for co-stimulation in the immune system?

Answer 27

Co-stimulators provide an opportunity for the body to regulate activation of T cells with homologous proteins to CD28.

Question 28

What is CTLA-4?

Answer 28

A prototype of inhibitory receptors for B7-1 ad B7-2 on APCs.

Question 29

What is PD-1?

Answer 29

An inhibitory receptor that recognizes different but structurally related ligands on many cell types.

Question 30

When are CTLA-4 and PD-1 induced?

Answer 30

In activated T cells. They provide negative feedback for the growth and proliferation of T cells. (inhibition of these in mice cause lymphocyte expansion and autoimmune disease)

Question 31

What important function do CTLA-4 and PD-1 have besides regulation of proliferation?

Answer 31

They inhibit responses to tumours. PD-1 inhibits responses to some chronic viral infections (blocking CTLA-4 or PD-1 is used to enhance immune responses to tumours)

Question 32

How are CD8 T cells activated?

Answer 32

Recognition of MHCI (may also require CD4+ helper T cells) Costimulation

Question 33

Which phenomenon is explained by the action of CD4 on CD8 T cells?

Answer 33

The diminished immune response seen in HIV patients.

Question 34

What happens to T cells after activation?

Answer 34

Accumulation of biochemical responses which result in elevated protein synthesis and expression of various signalling molecules (IL-2, IL-2 receptor, CD69, CD40 ligand, c-Fos)

Question 35

What happens at the immunological synapse?

Answer 35

Tight binding for a brief amount of time and an orderly redistribution of proteins in both APCs and T cell membranes at point of cell-to-cell contact.

Question 36

What does IL-2 do?

Answer 36

Autocrine growth stimulator

Question 37

What is the sequence of events that take place following receptor activation? (the signal transduction pathway)

Answer 37

Lck bound to CD4/CD8 receptor which instigates phosphorylation of CD3 zeta - ITAM regions. ZAP-70 then comes in and docks onto CD3 Zeta chain and binds to the phosphorylated ITAM part of CD3-zeta. ZAP70 then activates phosphorylation events of various adapter proteins and enzymes that assemble near TCR complex. One adapter protein, PLCγ1, activates the NFAT pathway and PI3-kinase activates mTOR which activates AP-1 and NFκB.

Question 38

Zap-70 and zeta pathway activates several pathways. What are these pathways?

Answer 38

Calcium-NFAT pathway Ras and Rac-MAP kinase pathways PKCθ-NFκB pathway PI3-kinase pathway

Question 39

What is the NFAT pathway?

Answer 39

A pathway that is triggered by an increase in cytosolic calcium. This pathways activates several genes including genes encoding T cell growth factor IL-2 and components of IL-2 receptor.

Question 40

What drug uses the NFAT pathway as a target to suppress the immune system?

Answer 40

Cyclosporine

Question 41

What does the PI3-Kinase pathway do?

Answer 41

A pathway that stimulates expression of anti-apoptotic proteins promoting survival of antigen stimulated T cells.

Question 42

What pathway is stimulated by phosphatidyl-inositol3 kinase?

Answer 42

Akt - mTOR which increases protein synthesis.

Question 43

What drug inhibits the PI3-kinase pathway?

Answer 43

Rapamycin which targets the mTOR pathway

Question 44

What are the functional responses of T cells to antigens and co-stimulation?

Answer 44

Cytokine release act on T cells and other cells involved in immune defenses. Cytokines function as mediators of immunity and inflammation.

Question 45

What does IL-2 do?

Answer 45

Promotes survival, proliferation and differentiation of effector and regulatory T cells.

Question 46

What cells produce IL-2?

Answer 46

CD4 and CD8 T cells (activated CD8+ T cells don't appear to produce large amounts of IL-2 but they do proliferate)

Question 47

What does IL-4 do?

Answer 47

B cell switching to IgE

Question 48

What cells produce IL-4?

Answer 48

CD4 and mast cells

Question 49

What does IL-5 do?

Answer 49

Activates eosinophils

Question 50

What cells produce IL-5?

Answer 50

CD4 T cells and mast cells

Question 51

What does IFN-γ do?

Answer 51

Activates macrophages

Question 52

what cells produce IFN-γ?

Answer 52

CD4 CD8 and NK cells

Question 53

What does IL-17 do?

Answer 53

Stimulates acute inflammation

Question 54

What cells produce IL-17?

Answer 54

CD4 CD8 and NK cells

Question 55

What does TGF-β do?

Answer 55

Inhibits T cell activation and differentiation of regulatory T cells

Question 56

What cells produce TGF-β?

Answer 56

CD4 T cells mainly and many other cell types

Question 57

When is IL-2 produced?

Answer 57

First produced within 1 - 2 hours after activation of the T cell

Question 58

What does activation do to affinity of IL-2 receptor?

Answer 58

It enhances the affinity of the cell for IL-2 by increasing production of IL-2R for strong binding.

Question 59

What kind of signalling molecule is IL-2?

Answer 59

Mostly an autocrine cytokine

Question 60

Why are CD8 T cells produced more rapidly than CD4 T cells?

Answer 60

Because CD8 T cells are important for actual killing of infected cells whereas CD4 T cells produce lots of cytokines without doing any killing

Question 61

What are the types of memory cells?

Answer 61

Central memory cells which populate lymphoid organs and are responsible for rapid clonal expansion after re-exposure to antigen. Effector memory cells localise in mucosal and other peripheral tissues that are essentially effector cells which can act rapidly on reinfecting antigens